Bronchopulmonary Dysplasia in Extremely Premature Infants: A Scoping Review for Identifying Risk Factors

Background: Over the years, bronchopulmonary dysplasia (BPD) affects the pulmonary function of infants, resulting in chronic health burdens for infants and their families. The aim of this scoping review was to screen available evidence regarding perinatal risk factors associated with the development and severity of BPD. Methods: The eligibility criteria of the studies were year of publication between 2016 and 2021; setting of a developed country; English or Japanese as the study language; and randomized controlled, cohort, or case-control design. The titles and abstracts of the studies were screened by independent reviewers. Results: Of 8189 eligible studies, 3 were included for severe BPD and 26 were included for moderate BPD. The risk factors for severe BPD were male sex, iatrogenic preterm birth, maternal hypertensive disorders of pregnancy (HDP), low gestational age, small-for-gestational-age (SGA) birth weight, mechanical ventilation on day 1, and need for patent ductus arteriosus (PDA) management. The risk factors for moderate or severe BPD included male sex, premature rupture of membranes, clinical chorioamnionitis, maternal HDP, SGA birth weight, bubbly/cystic appearance on X-ray, and PDA management. Conclusions: We identified several risk factors for BPD. We plan to confirm the validity of the new classification using the existing dataset.


Introduction
Bronchopulmonary dysplasia (BPD) is one of the most important chronic morbidities associated with prematurity [1,2]. It requires prolonged respiratory support and causes airway hypersensitivity [3] and obstructive pulmonary disease [4], resulting in an increased incidence of re-hospitalization [5], neurodevelopmental impairment [6], and pulmonary hypertension [7]. Over the years, these events have resulted in considerable chronic health burdens for infants and their families [8]. Due to significant improvements in the long-term prognosis of extremely premature infants [9], the number of BPD cases has increased. To avoid health deterioration and serious sequelae, it is important to identify the risk factors of BPD in premature infants and explore better prophylactic and treatment strategies for BPD.
Since BPD affects pulmonary function and neurodevelopmental outcomes, a classification that can be used to predict long-term prognosis is required. The BPD classification proposed in 2001 by the National Institute of Child Health and Human Development (NICHD) [10], which is based on clinical treatments, such as oxygen and ventilatory support, is widely used. However, the association between severity based on the NICHD classification and the long-term prognosis of infants is unclear, partly because the NICHD classification is consensus-based [11]. In 1992, a BPD classification based on etiology and chest X-ray findings was introduced in Japan [12]. An association between the Japanese classification and long-term outcomes has been reported [13], but to date, it is popular only in Japan [14]. We expect that unknown factors will fill the gaps in BPD definitions by combining the NICHD classification and the Japanese pathophysiology-based classification. Furthermore, the phenotype of BPD has changed since the introduction of antenatal corticosteroid and surfactant replacement therapy [15], and more premature newborns are managed using non-invasive positive pressure ventilation [16,17]. New modalities of respiratory support, such as the use of high-flow nasal cannulas, have also become popular [18]. Therefore, we believe that the Japanese pathophysiology-based BPD classification also needs to be revised to better reflect changes in phenotype and management [19].
We hope to develop a new pathophysiology-based BPD classification based on our original classification, which is internationally acceptable. The aim of this scoping review was to screen available evidence and identify perinatal risk factors associated with the development and severity of BPD to establish a novel BPD classification that can be used to predict long-term prognosis.

Search and Selection of Studies
With the aid of knowledgeable librarians, we created a search plan to locate eligible studies in PubMed and the Japanese database Ichushi Web. A search was conducted in October 2021 with no restrictions on date, time, language, document type, or publication status. Keywords were identified from experts' opinions, literature review, controlled vocabulary (Cumulative Index to Nursing and Allied Health Literature Headings, Medical Subject Headings, Excerpta Medica Tree), and a review of primary search results. To obtain all search outcome results and avoid poor reporting of outcomes, we did not limit the search in any way. The search strategy was developed with the assistance of a medical information specialist.

Eligibility Criteria
Articles that met the following eligibility criteria were included: (1) publication between January 2002 and August 2021; (2) setting of a developed country; (3) English or Japanese as the study language; (4) randomized controlled, prospective/retrospective cohort, or case-control study design; (5) extremely premature infants born before 28 weeks of gestation as study participants; and (6) endpoint of severe BPD according to the NICHD classification as an indicator of poor respiratory prognosis. Since we considered the development in the pathological evaluation and intervention/treatment methods of BPD and the change in the risk factors of BPD over the last 20 years, we only included articles published between January 2016 and August 2021. Regarding the secondary objective, we included studies that involved participants with birth weight < 1500 g or gestational age (GA) < 32 weeks and with endpoint of moderate or severe BPD according to the NICHD classification or combined results of BPD or death. The following types of articles were excluded from the review: (1) letters, editorials, commentaries, unpublished manuscripts, dissertations, government reports, books and book chapters, conference proceedings, meeting abstracts, lectures and addresses, and consensus development statements; (2) articles with <500 registered newborns; (3) articles reported by countries with United Nations Human Development Index < 0.8; and (4) animal studies.

Selection of Sources of Evidence
We used the web application Rayyan (http://rayyan.qcri.org; accessed on 1 January 2022) to speed up the selection process of studies for inclusion in this scoping review. The search results were de-duplicated using EndNote 20 and sent to four researchers for screening and confirmation. Four authors (S.K., M.I., M.S., and N.M.) independently screened all the titles and abstracts to exclude non-eligible trials. Disagreements between the four authors were discussed and resolved with the assistance of another reviewer. We then conducted a full-text review of potentially relevant articles. Disagreements between the reviewers were discussed, and decisions regarding selection were made by consensus. The reference lists of the included articles were screened for primary studies that were missed by the search strategy. Following a full-text review, data (including data on the risk factors of BPD) were extracted from all selected studies. We attempted to contact the author (HA) to conduct an additional study and provide the data [20].

Data Charting
At least two reviewers independently charted the data of the included studies using an Excel data extraction form developed for this study, and they discussed the results. The following data were extracted: author information, title, journal, year of publication, identified risk factors, study design, and participants. The review protocol was published [21] and registered on the University Hospital Medical Information Network Clinical Trial Registry (registration number: UMIN000045529). This scoping review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review Guideline [22].

Risk Factors of Severe BPD
Of the 8189 eligible studies, three were included for risk factors of severe BPD ( Figure 1). 2022) to speed up the selection process of studies for inclusion in this scoping revie search results were de-duplicated using EndNote 20 and sent to four research screening and confirmation. Four authors (S.K., M.I., M.S., and N.M.) indepen screened all the titles and abstracts to exclude non-eligible trials. Disagreements b the four authors were discussed and resolved with the assistance of another review then conducted a full-text review of potentially relevant articles. Disagreements b the reviewers were discussed, and decisions regarding selection were made by con The reference lists of the included articles were screened for primary studies th missed by the search strategy. Following a full-text review, data (including data risk factors of BPD) were extracted from all selected studies. We attempted to con author (HA) to conduct an additional study and provide the data [20].

Data Charting
At least two reviewers independently charted the data of the included studie an Excel data extraction form developed for this study, and they discussed the resu following data were extracted: author information, title, journal, year of publicatio tified risk factors, study design, and participants. The review protocol was publish and registered on the University Hospital Medical Information Network Clinic Registry (registration number: UMIN000045529). This scoping review was reporte cordance with the Preferred Reporting Items for Systematic Reviews and Meta-A Scoping Review Guideline [22].

Risk Factors of Severe BPD
Of the 8189 eligible studies, three were included for risk factors of severe BPD 1). The investigated prenatal risk factors of severe BPD included male sex [23], iat preterm birth (result of induced labor or a cesarean section before labor and/or rup membranes) [24], maternal hypertensive disorders of pregnancy (HDP) [23], low G and small-for-gestational-age (SGA) birth weight [23]   The investigated prenatal risk factors of severe BPD included male sex [23], iatrogenic preterm birth (result of induced labor or a cesarean section before labor and/or rupture of membranes) [24], maternal hypertensive disorders of pregnancy (HDP) [23], low GA [23], and small-for-gestational-age (SGA) birth weight [23]  The investigated postnatal risk factors of severe BPD included mechanical ventilation on the first day after birth and the need for patent ductus arteriosus (PDA) management [23,25] (Table 2). Mechanical ventilation on the first day after birth was found to be associated with the onset of BPD (aOR: 2.84, 95% CI: 1. 54-5.24). Furthermore, symptomatic PDA had a negative effect on BPD onset (aOR: 2.53, 95% CI: 1.41-4.53), but prophylactic treatment of PDA failed to show efficacy in BPD prophylaxis (aOR: 0.98, 95% CI: 0.53-1.81).
With our original search settings, the number of studies that investigated the association between severe BPD and various factors was small. Therefore, we revisited our original settings and adjusted the conditions (i.e., birth weight < 1500 g or GA < 32 weeks), any BPD severity, or combined results of BPD or death.

Discussion
To develop a new pathophysiology-based BPD classification that can be used to predict severe BPD early in life to facilitate early treatment, we conducted a scoping review and comprehensively evaluated the risk factors of BPD. We found that three previous studies were comparable to this study. The prenatal risk factors were male sex, iatrogenic preterm birth, maternal HDP, low GA, and SGA birth weight, and the postnatal risk factors were mechanical ventilation on the first day after birth and the need for PDA management. The risk factors of moderate or severe BPD included prenatal factors, such as male sex and SGA birth weight, and postnatal factors, such as RDS and PDA treatment. In addition, three of the included studies were conducted in Japan, and the risk factors mentioned in the studies included chorioamnionitis and bubble/cystic appearance. As previously reported, there are multiple risk factors for BPD; therefore, we reckoned that multiple factors should be extracted in this scoping review.
Unlike the international BPD classification, which is based on treatment, the Japanese BPD classification is based on etiological factors (e.g., RDS, intrauterine infection) and bubbly/cystic appearance on chest X-ray [12]. Imaging practices in neonatal intensive care units have not evolved significantly since Northway et al. reported an overview of BPD. Hirata et al. reported that bubbly/cystic appearance on chest X-rays was associated with respiratory prognosis [13]. We also found that bubbly/cystic appearance on chest X-ray was a risk factor for moderate or severe BPD. Therefore, we consider bubbly/cystic appearance on chest X-ray as a factor that can be used to develop a new BPD classification that can be used to predict severe BPD early in life, thereby facilitating early treatment.
Male sex had been reported to be a risk factor for BPD even before the articles included in this scoping review were published [54][55][56][57], and the results of our review are comparable to those of previous studies. Many articles on the relationship between SGA birth weight and BPD were extracted. It has been reported that biological mechanisms such as placental dysfunction and deficiency of insulin growth factor, vascular endothelial growth factor (VEGF), and VEGF receptors, which result in intrauterine growth retardation, can lead to fetal lung growth retardation [58].
In this scoping review, there were many studies that reported RDS as a risk factor for moderate or severe BPD, but some studies had contrary reports. In Japan, many institutions are attempting to improve the diagnosis of RDS by incorporating the prediction of surfactant secretion using a stable microbubble test [59,60]. However, the latest European guidelines recommend that surfactants be administered for RDS if sustained positive pressure ventilation fails [61]. This recommendation takes into account physical and radiographic findings but not surfactant secretion. Moreover, considering that most extremely premature infants are administered surfactants after birth using different methods [62][63][64], RDS may no longer be a necessary factor in the future diagnosis of BPD in extremely premature infants.
There is yet no consensus on whether chorioamnionitis increases the odds of developing BPD [14,[65][66][67]. PROM is regarded as the leakage of amniotic fluid before the onset of labor, and chorioamnionitis is an important factor [68]. It was suggested that the importance of chorioamnionitis in the diagnosis of BPD differs from country to country, and in this study, we found reviews of studies conducted in Japan and South Korea. Data on chorioamnionitis are extracted when a database is built in these two above-mentioned countries, which is an advantage. Pathological chorioamnionitis is thought to be associated with a high incidence of PROM and preterm birth [69]. However, symptoms of clinical chorioamnionitis and pathological chorioamnionitis are not always simultaneously present [70]. It was reported that the positive predictive value of pathological chorioamnionitis was high for uterine fundal tenderness and purulent or foul amniotic fluid or cervical discharge, but significantly low for maternal fever [71]. If chorioamnionitis is to be considered an onset factor of BPD, it may be necessary to decide on a more rigorous diagnostic method and selection criteria.
Due to factors such as pulmonary edema and endothelial injury because of increased pulmonary blood flow, increased risk of pulmonary hemorrhage, and the necessity of prolonged and aggressive ventilation, PDA is thought to have an adverse effect on the development of BPD [72]. Regarding PDA, there are various views on the diagnostic criteria, treatment methods, and indications for ligation. There are also reports that ibuprofen administration did not reduce the risk of developing BPD [73], or even increased it [74]. It is necessary to continue to focus on BPD prevention.
A limitation of this scoping review is the differences in the study design and patient characteristics between the articles. For practical reasons, this scoping review considered only articles written in English and Japanese. We also searched for articles in Japanese, but there were no such articles that were subject to review. Furthermore, due to the nature of the outlined search methodology, important published studies may have been omitted.
In conclusion, in this scoping review, we identified various prenatal and postnatal risk factors for moderate or severe BPD. Studies conducted in Japan and South Korea showed that chest X-ray findings and chorioamnionitis were predictors of BPD severity. These two factors should be combined to construct a new BPD classification that can be used to predict prognosis. In the future, we plan to use registry data to verify the prognosis predicted using the new BPD classification.